DE2331969C3 - Beta (3,4,5-trimethoxyphenyl) propionyltrile and process for its preparation - Google Patents

Description

H ₃ CO

H ₃ CO

characterized in that 1-amino-3,4,5-trimethoxybenzoi the formula

For the production of / ί-Aryl-propionitnlen, the one or more methoxy groups or hydroxyl groups

Wear s nen on the aromatic nucleus is, for example A method is known in which the correspondingly substituted methoxybenzene or the corresponding substituted hydroxybenzene are reacted with acrylonite, whereby the direct cyanoathylation of the

, o starting benzene derivative is achieved (A. Chatferjee and B.G. Hazra; "Tetrahedron Letters" 73 1969) Furthermore, the Anmcldenn has proposed a method according to the 3,4,5-trimethoxybenzaldehyde with cyanoacetic acid to / * - (3 4,5-Tnmethoxyphe-

nvD-acrylonitrile is implemented, which is then converted into Presence of a palladium-carbon catalyst is hydrogenated (Japanese patent application 9 783 /

H ₃ CO

H ₃ CO

^ -NH,

(11)

H ₃ CO

diazotized in a known manner and the resulting diazonium salt of 3,4,5-trimethoxybenzene then in the presence of a copper (I) halide or a copper (II) halide with Acrylonitrile to an 'i-halogen- / i- (3,4,5-trimethoxyphenyl) -piopionitrile the general formula

H ₃ CO

CH ₂ -CH-CN

(UI)

in which X denotes the halogen derived from the copper salt, and that the so obtained compound of the formula (III) then before or after separation from the Reaction mixture reductively dehalogenated in a manner known per se.

Uas the first-mentioned process of direct cyanoethylation of substituted benzene is for the Preparation of the ^ (3.4.5-trimethoxyphenyl) propionitrile not suitable, since it is very likely that the cyanoethyl group will be preferred in this reaction is installed in Ortho and Para position, so that ^ in the implementation of 1,2,3-trimethoxybenzene with "'Acrylonitrile the cyanoethyl groups in undesirable Positions in the benzene ring of the starting material so that, if any, the desired Compound of the formula (1) is obtained only in very low yields.

The second mentioned method is not necessary also an economically advantageous process, since it is used as the starting material used- 3,4,5-trimethoxybenzaldehyde difficult to prepare and also includes a catalytic hydrogenation which is difficult to regulate on an industrial scale.

To circumvent these difficulties, a Also a new and unique process for the production of H3,4.5-trimethoxyphenyl) propionitnls proposed this easily and commercially with high yields of the desired Product can be carried out.

The process proposed according to the invention for the preparation of the nitrile of the formula (I) exists in that l-amino-3,4,5-trime: hoxybenzene of the formula

H, CO

The invention relates to / i- (3,4,5-trimethoxyphenyl) propionitrile and a method for its production. The new compound has the following formula:

(H)

H ₃ CO

H ₃ CO

H ₃ CO

-CH ₇ -CH ₂ -CN (1)

H ₃ CO

is diazotized in a known manner and the resulting diazonium salt of 3,4,5-trimethoxybenzene in the presence of copper (l) halide or copper (II) halide with acrylonitrile to form a -halogen (M3,4,5-trimelhoxyphenyl) prop: onitrile the general formula

The compound (I) itself has antimicrobial activity and can also be used as an intermediate for the preparation of 2,4-diamino-5- (3 ', 4', 5'-trimethoxybenzyl) pyrimidine, the extraordinarily strong antibacterial activity of which is known (US -PS 26 58 897, 29 09 522, 30 49 544 and GB-PS 34 801, 8 75 562, 9 20 412 and 9 57 797). The prevention (I) can therefore be used directly as a drug or H ₁ CO

V-CH ₁ -CH-CN (III)

H ₃ CO

H ₃ CO

is implemented in the X for that from the copper salt

originating halogen, this nitrile of the formula (IU) then before or after Isolierunu is reductively dehalogenated from the reaction mixture in a manner known per se.

During the diazotization of 1-amino-OAS-trimethoxybenzene In the process according to the invention, the diazonium salt of 3,4,5-trimethoxybenzene is used the general formula

HXO

H ₃ CO - (Υ N = NX (IV)

H ₃ CO

formed in which X is the acid residue of the diazotization mineral acid used means. The implementation of the diazonium salt with the acrylonitrile is a Meerwein condensation in which the originally in the starting material, the l-amino-3,4,5-trimeihoxybenzene. any 1-amino group present was finally exchanged for a 2-halo-2-cyanoethyl group can be. So far the opinion was that the efficiency of the Meerwein condensation with Benzene derivatives, which carry a methoxy group on the core, is lower than door benzene derivatives, which one electron-sucking groups, for example a nitro group or chlorine, contain (Brunner and P e r g e r, "Monatsh." 79, p. 187, 1948). Accordingly this doctrine is the preparation of / 5-phenylpropionitrile derivatives with 3 methoxy groups on the benzene ring using the Meerwein condensation has neither been attempted nor carried out. In view of this situation, it is all the more surprising that, contrary to expectations, the implementation of the diazonium salt of 3,4,5-trimethoxybenzene with acrylonitrile by the Meerwein process despite the presence the three methoxy groups on the benzene ring of 3,4,5-trimethoxybenzene runs smoothly with high yield, so that also the a-halogen- / i- (3,4,5-trimethoxyphenyl) -propionitrile with a high yield and thus also the end product of the formula (I) with an extremely high yield Overall yield of the process can be obtained. The procedure is carried out in two stages, namely in the first stage of the Meerwein condensation and the subsequent stage of the reductive Dehalogenation. For the Meerwein condensation, the l-amino-3,4,5-trimethoxybenzene is used in one Mineral acid, for example in hydrochloric acid, or in a mixture of mineral acids and organic Acids, for example in a mixture of hydrochloric acid and acetic acid, dissolved. In the so received Solution becomes a lower nitrogen salt, for example sodium nitrite, at 5 ° C or lower temperature added, with the diazotization of 1-amino-3,4,5-trimethoxybenzene goes smoothly. The reaction mixture of the diazotization is then with an acrylonitrile solution and a copper salt in Acetone at low temperature, preferably at a temperature below 0 ° C and preferably in an inert gas atmosphere, for example in a nitrogen atmosphere. The mole ratio of the Acrylonitrile to 1-amino-3,4,5-trimethoxybenzene can preferably be 4: 1 to 5: 1. As a mineral acid In addition to hydrochloric acid, hydrobromic acid and others can also be used. As copper salt come copper (I) chloride, copper (II) chloride, Copper (I) bromide, copper (II) bromide and others in question. The diazotization is preferably carried out in the presence a small amount of alkali metal chloride, for example in the presence of a small amount of lithium chloride.

The Meerwein condensation produces an a-halogen- / J- (3,4,5-trimethoxypheny!) - propionitrile of the general formula (III), which is subjected to the reductive dehalogenation to the nitrile of the formula (I). the reductive halogenation can be carried out, for example, in such a way that zinc powder or zinc granules are added directly to the reaction mixture obtained from the Meerwein condensation and the mixture is then stirred at room temperature. This creates hydrogen in the reaction mixture released, which reductively dehalogenates the α-halogen compound (III). Alternatively, the α-halo / J- (3,4,5-trimethoxyphenyl) propionitrile initially from the reaction mixture obtained from the Meerwein condensation, for example by extraction with benzene and stripping off the solvent under reduced pressure. That so isolated Nitrile can then be dissolved in acetic acid and this solution with the metallic zinc in powder or form Granulate form are added. Here, too, the hydrogen is developed, which reductively the nitrile dehalogenated.

The 1-amino-3,4,5-trimethoxybenzene used as the starting product can be easily and simply obtained by using trimethylgallamide subjected to the Hoffmann reaction (C. Graebe and Moritzsuter, "Ann. Chem." 340, p. 222 [1905]). The starting compound can also be obtained directly by reacting nitromethane or sodium azide can be obtained with trimethylgallic acid in polyphosphoric acid solution.

The /? - (3,4,5-TrimethoxyphenyI) -propionitrile obtained as the end product of this process has, as already Mentioned at the beginning, antibacterial or antimicrobial activity. In the table below the minimum amounts of the compound (I) are given, which the growth of various bacteria and stop mushrooms.

Antimicrobial activity

of /? - (3,4,5-trimethoxyphenyl) propionitrile

Tested microorganisms Minimal Active concentrations tration (mcg / ml) Bacteria Shigella sonnei 320 Shigella flexneri 320 Salmonella typhi 160 Staphylococcus aureus 320 Fungi Trichophyton mentagrophytes 80

The high superiority of the effect of the invention, Connection results? I from the following comparison test:

Tested microorganisms

Minimal active concentration ?, "- Diamino- ! ration fcg / ml) 5- (3 ', 4 \ 5'-tri- Connection methoxy according to benzyl) - Claim 1 pyrimidine (Comparison) 500 800 160 80

Salmonella typhi

Trichophyton 80 800

mentagrophytes

The invention is described in more detail below on the basis of exemplary embodiments.

example 1

1. 7.4 g of 1-amino-3,4,5-trimethoxybenzene were added to a mixture of 8.6 ml of 35% strength hydrochloric acid. 15.6 ml of acetic acid and 42 ml of water dissolved. The solution was then added at 0-5 C ^G in small portions with 2.8 sodium nitrite for the diazotization. The diazonium salt solution thus obtained was then placed in a nitrogen atmosphere at - 1O ⁰ C added dropwise to a solution of 0.5 g of copper (I) chloride, 0.3 g of lithium chloride and 20 g acrylonitrile in 230 ml of acetone. After addition of the diazonium salt solution, the mixture was stirred for 5 hours at 0-5 ⁰ C. After the reaction mixture was left to stand overnight, it was extracted with benzene. The benzene extract was washed several times with water and then shaken with 2N aqueous sodium hydroxide solution and finally again with water and a saturated aqueous sodium chloride solution. The benzene extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 8.6 g of α-chlorine - /? - (3,4,5-trimethoxyphenyl) propionitrile were obtained as a pale yellow oil. The yield was 83.5%. After adding η-hexane, the oil could be completely crystallized. The crystals had a melting point of 88-89 ⁰ C. After recrystallization from a 1: 1 mixture of isopropyl alcohol and hexane gave a crystalline product with a melting point of 89 ° C. The product had the following elemental analysis:

50

C ₁₂ H ₁₄ ClNO ₃ : . C. 56.51. H 5.52. N 5.50 Found .. . C. 56.48. H 5.53, N 5.48 calculated ..

The resulting reaction mixture was filtered off from the remaining zinc and the Hitrat with benzene and Water added. The mixture thus obtained was stirred and divided into benzene and aqueous Phase separated. The benzene phase was twice with 10% hydrochloric acid, then twice with 10% aqueous sodium hydroxide solution and finally with water and a saturated aqueous sodium chloride solution washed. The benzene solution thus obtained was then poured over anhydrous magnesium sulfate dried and concentrated by distillation under reduced pressure. 4.5 g /? - (3,4,5-Trimethoxyphenyl) -propionitrile as colorless obtained oil in a yield of 86.6%. When left standing the oil thus obtained gradually solidified. The final product showed the following elemental analysis:

C ₁ ^ H ₁₅ NO ₃ :

The NMR spectrum in CDCl ₃ as solvent showed the following maxima:

-CH ₂ -, Λ = 3.23 ppm (doublet),
- CHCl -, Λ = 4.56 ppm (triplet).

2. 6 g of (/-Chlor-//-(3.4,5-trimethoxyphenyl) propionitrile were dissolved in 60 ml of acetic acid, and 12 g of metallic zinc powder were added. The mixture was stirred at room temperature for 3 hours ... C 65.14, H 6.87, N 6.32%;
calculated ... C 65.20, H 6.84. N 6.33%.

Example 2

The procedure described in Example 1 under (1) was repeated with the modification that instead of 0.5 g copper chloride 0.9 g copper (II) chloride dihydrate were used. 8.4 g of α-chloro / i- (3,4,5-trimethoxyphenyl) propionitrile were thereby obtained corresponding to a yield of 81.6% obtained in crystalline form.

The intermediate product thus obtained was described in the same manner as in Example 1 under (2), processed further to give the desired end product of the formula (I).

Example 3

7.4 g of l-amino-3,4,5-trimethoxybenzene were diazotized in the same way as described in Example 1 under (1). The solution of the diazonium salt thus obtained was added dropwise to a solution of 0.5 g of copper (I) chloride, 0.3 g of lithium chloride and 20 g of acrylonitrile in 230 ml of acetone in a stream of nitrogen and while cooling the mixture to -10 ^° C. After the addition, the resulting mixture was stirred at 0-5 ° C for an additional 5 hours. The reaction mixture, which contained α-chlorine - /? - (3,4,5-trimethoxyphenyl) propionitrile obtained in this way, was left to stand overnight and then 16 g of zinc powder were added. The mixture was stirred for 2 hours at room temperature, the -chloro- / M3,4,5-trimethoxyphenyl) propionitrile being reductively dehalogenated. The reaction mixture was extracted with benzene. The extract obtained as a benzene solution was washed several times with water, then with 2N aqueous sodium hydroxide solution and finally with water and a saturated aqueous sodium chloride solution. The benzene solution thus washed was dried over anhydrous sodium magnesium and then concentrated under reduced pressure. 7.2 g / i- (3,4,5-trimethoxyphenyl) propionitrile were obtained in a yield of 80.7%. based on the l-amino-3,4,5-trimethoxybenzene used, obtained as an oil.

Claims (2)

The following are regarded as an intermediate drug product: 1. / H3,4,5-trimethylphenyl) propionitrile. 2. Process for the preparation of 0- (3,4,5-Tnmethoxyphenyl) -propionitril the formula H ₃ CO